The online version of this article has a Supplementary Appendix. BackgroundFollowing a clinical evaluation of deferasirox (Exjade ® ) it was concluded that, in addition to baseline body iron burden, ongoing transfusional iron intake should be considered when selecting doses. The 1-year EPIC study, the largest ever investigation conducted for an iron chelator, is the first to evaluate whether fixed starting doses of deferasirox, based on transfusional iron intake, with dose titration guided by serum ferritin trends and safety markers, provides clinically acceptable chelation in patients (aged ≥2 years) with transfusional hemosiderosis from various types of anemia. Design and MethodsThe recommended initial dose was 20 mg/kg/day for patients receiving 2-4 packed red blood cell units/month and 10 or 30 mg/kg/day was recommended for patients receiving less or more frequent transfusions, respectively. Dose adjustments were based on 3-month serum ferritin trends and continuous assessment of safety markers. The primary efficacy end-point was change in serum ferritin after 52 weeks compared with baseline. ResultsThe 1744 patients enrolled had the following conditions; thalassemia (n=1115), myelodysplastic syndromes (n=341), aplastic anemia (n=116), sickle cell disease (n=80), rare anemias (n=43) and other transfused anemias (n=49). Overall, there was a significant reduction in serum ferritin from baseline (-264 ng/mL; P<0.0001), reflecting dosage adjustments and ongoing iron intake. The most common (>5%) adverse events were gastrointestinal disturbances (28%) and skin rash (10%). ConclusionsAnalysis of this large, prospectively collected data set confirms the response to chelation therapy across various anemias, supporting initial deferasirox doses based on transfusional iron intake, with subsequent dose titration guided by trends in serum ferritin and safety markers (clinicaltrials.gov identifier: NCT00171821).

Cardiac iron overload causes most deaths in ␤-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with ␤-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n ‫؍‬ 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n ‫؍‬ 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean ؎ coefficient of variation) improved from a baseline of 11.2 ms (؎ 40.5%) to 12.9 ms (؎ 49.5%) (؉16%; P < .001). LVEF (mean ؎ SD) was unchanged: 67.4 (؎ 5.7%) to 67.0 (؎ 6.0%) (؊0.3%; P ‫؍‬ .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (؎ 25.6%) to 32.5 ms (؎ 25.1%) (؉2%; P ‫؍‬ .57) and LVEF increased from baseline 67.7 (؎ 4.7%) to 69.6 (؎ 4.5%) (؉1.8%; P < .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials. gov as NCT00171821. (Blood. 2010;115: 2364-2371)

BackgroundProspective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important. Design and MethodsSeventy-one patients in the EPIC cardiac substudy elected to continue into the 3 rd year, allowing cardiac iron removal to be analyzed over three years. ResultsMean deferasirox dose during year 3 was 33.6±9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ±39.1% at baseline to 17.1 ms ±62.0% at end of study (P<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43±1.2 mg Fe/g dry weight (dw) at baseline to 1.80 ±1.4 mg Fe/g dw at end of study (P<0.001). After three years, 68.1% of patients with baseline T2* 10 to <20 ms normalized (≥20 ms) and 50.0% of patients with baseline T2* >5 to <10 ms improved to 10 to <20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drugrelated adverse event in year 3 was increased serum creatinine (n=9, 12.7%). ConclusionsThree years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1% (32 of 47) of patients with T2* 10 to <20 ms.

Purpose Although IKZF1 deletion ( IKZF1) confers a higher risk of relapse in childhood B-cell acute lymphoblastic leukemia (B-ALL), it is uncertain whether treatment intensification will reverse this risk and improve outcomes. The Malaysia-Singapore ALL 2010 study (MS2010) prospectively upgraded the risk assignment of patients with IKZF1 to the next highest level and added imatinib to the treatment of all patients with BCR- ABL1 fusion. Patients and Methods In total, 823 patients with B-ALL treated in the Malyasia-Singapore ALL 2003 study (MS2003; n = 507) and MS2010 (n = 316) were screened for IKZF1 using the multiplex ligation-dependent probe amplification assay. The impact of IKZF1 on the 5-year cumulative incidence of relapse (CIR) was compared between the two studies. Results Patient characteristics were similar in both cohorts, including IKZF1 frequencies (59 of 410 [14.4%] v 50 of 275 [18.2%]; P = .2). In MS2003, where IKZF1 was not used in risk assignment, IKZF1 conferred a significantly higher 5-year CIR (30.4% v 8.1%; P = 8.7 × 10), particularly in the intermediate-risk group who lacked high-risk features (25.0% v 7.5%; P = .01). For patients with BCR-ABL1-negative disease, IKZF1 conferred a higher 5-year CIR (20.5% v 8.0%; P = .01). In MS2010, the 5-year CIR of patients with IKZF1 significantly decreased to 13.5% ( P = .05) and no longer showed a significant difference in patients with BCR-ABL1-negative disease (11.4% v 4.4%; P = .09). The 5-year overall survival for patients with IKZF1 improved from 69.6% in MS2003 to 91.6% in MS2010 ( P = .007). Conclusion Intensifying therapy for childhood B-ALL with IKZF1 significantly reduced the risk of relapse and improved overall survival. Incorporating IKZF1 screening significantly improved treatment outcomes in contemporary ALL therapy.